Patients affected with Alzheimer's disease suffer from severe neuronal damage, manifested by progressive memory loss and cognitive deterioration. Alzheimer's patients, who are currently untreatable, may benefit from the endogenous de novo generation of neurons, if we are able to understand the mechanisms that regulate neurogenesis, and how to manipulate them. Presenilin-1 (PS1) is a multi-pass protein that plays a major role in the aspartyl protease 3-secretase. Mutations in the gene encoding PS1 cause Familial Alzheimer's disease (FAD). Recent evidence suggests that PS1 plays a role in adult neurogenesis. To gain an insight into the role of PS1 in neurogenesis, a process that takes place in discrete areas of the adult brain, we developed a lentiviral vector system that expresses small interfering RNAs (siRNA) for PS1 targeting, and green fluorescent protein for the tracking of transduced cells. We show that stereotaxic injection of these lentiviral vectors into neurogenic areas in the adult brain dramatically reduces neural stem cell proliferation and induces astrocyte differentiation. Based on our intriguing preliminary results we hypothesis that PS1 plays a major role in neural stem cell proliferation and cell fate determination in the adult brain. In Specific Aim 1 we propose to determine the role of PS1 in regulation of neural stem cell proliferation, migration and cell fate determination by examining the effect of PS1 silencing on neural stem cells in the adult brain. In Specific Aim 2 we propose to define the role of PS1 in regulation of the neurogenic niche and of intrinsic pathways in neural stem cells. This will be achieved by expression of siRNA for PS1 silencing in a cell type-specific manner, in nestin-expressing neural stem cells and glial fibrillary acidic protein-expressing astrocytes. In Specific Aim 3 we propose to determine the role of PS1 in learning and memory in the adult brain. Using behavioral analysis, the effect of PS1 silencing in neural stem cells in neurogenic areas on learning and memory processes will be examined. In Specific Aim 4 we propose to determine the effect of FAD-linked mutant PS1 on adult neurogenesis by the generation of transgenic mice that will express FAD-linked PS1 variants in neural stem cells exclusively in the adult brain. This study proposes powerful approaches for the determination of the role of PS1 in neurogenesis and of the effect of Alzheimer's pathology on this process. These studies may have far-reaching therapeutic implications in the aging and Alzheimer's brain. PUBLIC HEALTH RELEVANCE: Modulation of neurogenesis holds great promise as a therapeutic strategy. The ability to induce formation of new neurons and support their functional integration in local circuits may compensate for loss of degenerating neurons and memory impairments, characterizing Alzheimer's disease (AD). This project will investigate the role of a critical player in AD, namely, presenilin-1 (PS1) in regulating neurogenesis in the adult brain. The results of these studies may provide strategies to treat or prevent the development of the human illness.